Huntington's disease (H.D.) is an autosomal dominant neurological disorder characterized by late life onset of chorea, memory less and dementia. During the last two years we have searched for the mutant protein in H.D. by 2-dimensional gel electro@horesis of many different brain and non-neural tissues. The genetic prediction, based on a single amino acid substitution in the mutant protein, is that there would be a single spot in normals and a double spot in H.D. After 1,700 gels we found a likely candidate in a perchloric acid extract of the putamen and caudate. A major spot and two minor satellite spots were present in the normal and two major spots and four minor satellites were present in H.D. These have been termed Hd AI, II and III and Hd Duarte I, II and III respectively. A similar mutant protein was present in the brains of patients with classical schizophrenia. We have termed this Hd SI, II and III. We interpret this to indicate that H.D. and schizophrenia are allelic mutations of the same gene. These mutations were not present in normals or brains of patients with other neurological diseases. The purpose of this grant is to isolate these proteins, determine the type of modification of the Hd A II and III proteins, determine the amino acid substitution in Hd Duarte and Hd S, examine the distribution of these proteins in the brain and the exact cellulr location of the Hd protein, determine whether the Hd protein is expressed in non-neural tissues, and whether other hereditary neurological disorders such as tuberous sclerosis, maniac-depressive psychosis, and the hereditary ataxias are mutations of the same or similar protein.